PROJECT 4 Despite genetic and epidemiological data implicating maternal exposures and neuroimmune mechanisms as a risk factor for schizophrenia (SZ) and the development of maternal immune activation (MIA) animal models of altered neurodevelopment, little is known about the specific mechanisms by which MIA leads to altered brain development, connectivity and behavior. Project 4 will address this critical gap in our knowledge by pursuing two Specific Aims related to the role of neural inflammation in MIA and SZ. Informed by our preliminary studies that found evidence of cortical inflammation and increased striatal pre-synaptic dopamine (DA) in MIA nonhuman primates (NHPs), Aim 1 will use Positron Emission Tomography (PET) and magnetic resonance imaging (MRI) in a new cohort of MIA NHPs to investigate the developmental course of inflammation and increased striatal DA, and their relationship to abnormal social interactions and cognition in these animals. Further, this aim will test a neurodevelopmental model in which cortical inflammation measured using [18F]PBR 111 PET during childhood precedes the development of increased subcortical DA measured using [18F] fluoromethyltyrosine (FMT) PET and worsening atypical behaviors after puberty.
Aim 2 will investigate the clinical significance of the MIA model by using MRI-based measures of neuroinflammation (diffusion-based measurement of free water, glutathione spectroscopy) that will be also obtained longitudinally in the NHP's as well as in patients with first-episode SZ. Successful completion of this study will provide new insights into the developmental neurobiology of brain inflammation in the MIA NHP and the relationship between inflammation, excessive subcortical DA, and changes in social behaviors and cognition in these animals. Direct comparison of the NHP model and humans with first-episode SZ on MRI markers of brain inflammation will provide an important test of the clinical significance of the MIA model.
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